title: Disruption of the transient receptor potential vanilloid 1 can affect survival, bacterial clearance, and cytokine gene expression during murine sepsis.
abstract: BACKGROUND
  Previous studies suggest that the transient receptor potential vanilloid 1 (TRPV1) channel has a role in sepsis, but it is unclear whether its effect on survival and immune response is beneficial or harmful.
  
  
  METHODS
  We studied the effects of genetic (Trpv1-knockout vs. wild-type [WT] mice) and pharmacologic disruption of TRPV1 with resiniferatoxin (an agonist) or capsazepine (an antagonist) on mortality, bacterial clearance, and cytokine expression during lipopolysaccharide or cecal ligation and puncture-induced sepsis.
  
  
  RESULTS
  After cecal ligation and puncture, genetic disruption of TRPV1 in Trpv1-knockout versus WT mice was associated with increased mortality risk (hazard ratio, 2.17; 95% CI, 1.23-3.81; P = 0.01). Furthermore, pharmacologic disruption of TRPV1 with intrathecal resiniferatoxin, compared with vehicle, increased mortality risk (hazard ratio, 1.80; 95% CI, 1.05-3.2; P = 0.03) in WT, but not in Trpv1-knockout, mice. After lipopolysaccharide, neither genetic (Trpv1 knockout) nor pharmacologic disruption of TRPV1 with resiniferatoxin had significant effect on survival compared with respective controls. In contrast, after lipopolysaccharide, pharmacologic disruption of TRPV1 with capsazepine, compared with vehicle, increased mortality risk (hazard ratio, 1.92; 95% CI, 1.02-3.61; P = 0.04) in WT animals. Furthermore, after cecal ligation and puncture, increased mortality in resiniferatoxin-treated WT animals was associated with higher blood bacterial count (P = 0.0004) and higher nitrate/nitrite concentrations and down-regulation of tumor necrosis factor α expression (P = 0.004) compared with controls.
  
  
  CONCLUSIONS
  Genetic or pharmacologic disruption of TRPV1 can affect mortality, blood bacteria clearance, and cytokine response in sepsis in patterns that may vary according to the sepsis-inducing event and the method of TRPV1 disruption.
authors.affiliation: Department of Perioperative Medicine, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Guptill
authors.forename: Xizhong
authors.initials: X
authors.lastname: Cui
authors.forename: Alfia
authors.initials: A
authors.lastname: Khaibullina
authors.forename: Jason M
authors.initials: JM
authors.lastname: Keller
authors.forename: Nicholas
authors.initials: N
authors.lastname: Spornick
authors.forename: Andrew
authors.initials: A
authors.lastname: Mannes
authors.forename: Michael
authors.initials: M
authors.lastname: Iadarola
authors.forename: Zenaide M N
authors.initials: ZM
authors.lastname: Quezado
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000187:drug effects* / Q000235:genetics; D002211:Capsaicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002432:Cecum / Q000601:surgery; D016207:Cytokines / Q000097:blood / Q000187:drug effects* / Q000235:genetics; D004195:Disease Models, Animal; D004224:Diterpenes / Q000008:administration & dosage; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D008026:Ligation; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010533:Peritoneal Lavage; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D050916:TRPV Cation Channels / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha
chemical_list: D016207:Cytokines; D004224:Diterpenes; D008070:Lipopolysaccharides; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C024353:resiniferatoxin; C071423:capsazepine; D002211:Capsaicin